The polymerization process for many polymers susceptible to oxidation, e.g. polyvinylpyrrolidones, for example homo- and copolymers of N-vinylpyrrolidone, is usually followed by spray drying or drum drying or another hot-air drying process to convert the materials into free-flowing powders. During these processes, the intimate contact with air, and the heat, leads to formation of traces of peroxides, the content of which increases still further during the course of subsequent packaging and storage. This tendency toward peroxide formation may pose problems during use in pharmaceutical preparations. Comparable problems also arise with polyethers or polyamides. Examples of further oxidative effects are discoloration of the polymers and changes in molecular weight.
By way of example, the peroxide content for said polyvinylpyrrolidones is limited to a maximum of 400 ppm in the current pharmacopeias, e.g. Ph. Eur. 6, and JP XIV. Although the kinetics of peroxide formation can be slowed by drying in the absence of air, storage at low temperatures, or hermetically sealed packaging in vacuo or under an inert gas, these methods cannot prevent peroxide formation. Furthermore, said methods are very costly, and are therefore unpopular with users.
Many previous attempts have been made to provide chemical stabilization of polymers susceptible to oxidation, in order to prevent peroxide formation.
It is well known that antioxidants can be used to prevent undesired oxidative processes, examples being phenolic antioxidants, ascorbic acid, ethoxyquin, butylhydroxytoluene, butylhydroxyanisol, tocopherol, or nordihydroguaiaretic acid (NDGA). It is also known that phenolic antioxidants have only limited suitability, because of their lack of biodegradability (cf. Römpp-Chemie-Lexikon [Rompp's Chemical Encyclopedia], 9th edition, Georg Thieme Verlag, Stuttgart, 1992).
U.S. Pat. No. 6,331,333 discloses that polyvinylpyrrolidones are stored in packaging impermeable to oxygen, in the presence of an oxygen scavenger, in order to prevent peroxide formation during storage. Oxygen scavengers used are ascorbic acid, iron powder, or iron salts. There is spatial separation here between oxygen scavengers and polyvinylpyrrolidone.
U.S. Pat. No. 6,498,231 discloses that polyvinylpyrrolidones are mixed with an antioxidant for stabilization during storage and are stored under an atmosphere comprising no more than 50 000 ppm of oxygen. Examples of antioxidants used are phenolic or bisphenolic compounds, preferably thioamide derivatives or thiourea derivatives. However, antioxidants of this type are not entirely free from physiological risk and are quite unsuitable if the polymers are to be used in pharmaceutical preparations.
GB 836,831 discloses a method for the stabilization of polyvinylpyrrolidones with respect to discoloration, by treating solutions of the polymers with sulfur dioxide, sulfurous acid, or alkali metal sulfites. However, it has been found that use of this method actually leads, after storage, to more peroxide formation than in untreated polymers.
EP-B 1083 884 describes a method for the stabilization of polyvinylpyrrolidones with respect to peroxide formation by admixing very small amounts of heavy metals, or enzymes that cleave peroxides, with aqueous solutions of the polymers. However, the use of heavy metals is disadvantageous because of the possibility of accumulation of the heavy metals in the body. The use of enzymes is disadvantageous mainly for reasons of costs and stability.
Furthermore, however, chemical stabilization has proven unsuccessful specifically with crosslinked polymers, such as crospovidone.
Another way of suppressing autoxidation of polymers susceptible to oxidation is to keep the polymers in oxygen-impermeable packaging, after work-up.
EP-B 873 130 recommends spray-drying polyvinylpyrrolidones in a nitrogen atmosphere to prevent peroxide formation and keeping them in airtight containers.
Composite foils composed of polyethylene and aluminum are also used as packaging material for substances susceptible to oxidation. Although films of this type in principle have good barrier properties, because they are in essence impermeable to oxygen, they have the disadvantage that mechanical damage to the barrier layer is practically impossible to avoid during handling, and can lead to severe impairment of the barrier property. Even microcracks are enough to impair the impermeability of the foils to oxygen.
JP-A 09-226070, JP-A 2000-44756, JP-A 09-216653, or JP-A 2002-3609 disclose composite foils with polyvinyl alcohol layers and their use for oxygen-impermeable packaging of foods, cosmetics, detergents, chemicals, or fuel.
WO 2006/015765 discloses tubular multilayer thermoplastic composite foils for the packaging of foodstuffs.